While the health risks of smoking are well known, vital questions remain about tobacco use, smoking cessation, and the health benefits of cessation in today's smokers. The proposed research addresses these questions via three primary specific aims: 1) Produce new data on how to treat smoking optimally by conducting a comparative effectiveness trial that for the first time directly contrasts the two smoking cessation pharmacotherapies with the strongest extant evidence of efficacy (combination NRT and varenicline); 2) Determine the impact of smoking cessation in today's smokers on biomarkers and health risk factors, especially for cardiovascular disease (CVD), which will elucidate the mechanisms by which cessation benefits health; and, 3) Identify individuals who are at greatest risk for exacerbation of biomarkers or risk factor status due to continued smoking, and who benefit most from cessation. The proposed research will address two secondary aims: 1) to develop a treatment assignment algorithm for the optimal treatment of today's smokers; and, 2) to determine the relation of health biomarkers to disease outcomes such as CVD events. These aims must be addressed in a contemporary population of smokers because today's smokers differ from smokers in earlier studies on the basis of weight, sex distribution, diet, socioeconomic status, and other factors that might affect the risks and the health effects of cessation. We will recruit 900 persons from an ongoing longitudinal study of smoking and health (continuing participants, including both smokers and successful quitters), and 600 new, current smokers for this trial (newly recruited participants), providing 1500 total participants for this new study. All of the newly recruited and some of the continuing participants (total N=1150), will enroll in a comparative effectiveness trial that directly compares the two most effective smoking cessation therapies (varenicline vs. combination nicotine replacement therapy: N=475 for each treatment) with one another, and with an active comparator treatment (the nicotine patch; N=200). All participants (N=1500) will be evaluated for a minimum of 3 years. The total time for assessing biomarkers and health outcomes will 3-4 years for newly recruited participants and 8-9 years for the continuing participants. Biomarkers of disease risk will focus on CVD markers (e.g., carotid thickness, arterial stiffness, stress testing, inflammation) including measures for all major risk factors for CVD. We will use these and other measures to identify smokers who are most likely to benefit from cessation, and to identify etiologies (i.e., atherosclerosis progression, arterial stiffening, and oxidant stress) for adverse, smoking-related health events. In sum, this research will produce important new data on the treatment of smoking, the mechanisms of smoking-related disease, the benefits of cessation, and identification of smokers who are at greatest risk for an adverse CVD or other health events. While all smokers should quit, our findings could ultimately help focus treatment and motivate smokers and clinicians to intervene more intensively with patients at greatest risk.